6533b7d9fe1ef96bd126cbb8

RESEARCH PRODUCT

PATHOGENESIS OF HUMAN LEUKOCYTE ANTIGEN B27–POSITIVE ARTHRITIS

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Acute reactive arthritis, spondyloarthropathy (SpA) in association with chronic inflammatory bowel disease (IBD) and ankylosing spondylitis (AS), although differing in individual presentation and in the natural course of disease, have in common a strong association with human leukocyte antigen (HLA)-B27 and a possible involvement of other genetic and also environmental factors. This group of related diseases belonging to the seronegative SpAs represents the clearest example of HLA class 1–linked disease in humans. Several newly emerging animal models of the SpAs, which have been reviewed in this issue of the Rheumatic Disease Clinics of North America , have permitted us to investigate the immunologic basis of HLA-B27 transgenic rat and mouse diseases. In contrast to studies in humans, these models allow modifications of single genetic or environmental factors and to study the consequences of such modifications on the incidence or the course of SpA-like diseases in rodents; however, the complexity of human disease with the interplay of multiple microbial and host genetic factors can only be in part mimicked by an animal model. Therefore, much of our current understanding of the etiopathogenesis of the SpAs results from careful studies of the host-microbial interplay in human disease, namely in bacteria-induced reactive arthritis, the "human model" of HLA-B27 associated SpAs. Clinical material from peripheral blood, synovial fluid, and membranes and from the sacroiliac joints can directly be investigated by bacteria or cytokine-specific polymerase chain reaction (PCR) or immunohistology and can be cultured in vitro to characterize T lymphocytes and synovial fibroblasts involved. This article reviews recent immunologic work done in human SpAs. The crucial question of how HLA-B27 can induce disease still remains unanswered. The main theories trying to explain the mechanisms of the association of B27 with SpA are as follows: 1Promotion of bacterial persistence: HLA-B27 favors persistence of bacteria and impairs antibacterial defenses. 2Arthritogenic peptide: A cross-reactive peptide from intracellular bacteria is presented by HLA-B27 and triggers autoimmunity in the joint. 3Altered self: HLA-B27 contains a highly reactive cysteine residue at position 69 within the peptide binding groove, which could easily form disulfide bonds with homocysteine. Such modified HLA-B27 antigens are recognized by cytotoxic T lymphocytes (CTLs) as foreign. 4HLA-B27 as autoantigen: HLA-B27 derived peptides cross-reactive with epitopes from bacteria are presented on HLA-class 2 antigens and trigger autoimmunity. The different hypotheses discussed do not necessarily exclude each other, and experimental evidence to support these theories in human disease have been published for any of the hypotheses. In Figure 1, the current concepts of the pathogenesis of reactive arthritis are summarized as a human "model disease" of the SpAs with known bacterial trigger and the possible contribution of HLA-B27 during the process of disease.